Intensive Care Med

DOI 10.1007/s00134-014-3515-1

UNDERSTANDING THE DISEASE

Tom E. Fletcher
Robert A. Fowler
Nicholas J. Beeching

Understanding organ dysfunction

in Ebola virus disease

Received: 19 September 2014

Accepted: 6 October 2014

T. E. Fletcher
WellcomeTraining Fellow and Lecturer,
Liverpool School of Tropical Medicine,
Pembroke Place, Liverpool L3 5QA, UK
e-mail: tomfletcher@doctors.org.uk

Springer-Verlag Berlin Heidelberg and

ESICM 2014

R. A. Fowler
Associate Professor of Medicine,
Sunnybrook Hospital, University of
Toronto, 2075 Bayview Avenue, Room
D478, Toronto, ON M4N 3M5, Canada
e-mail: Rob.Fowler@sunnybrook.ca

N. J. Beeching ())
Senior Lecturer in Infectious Diseases,
Liverpool School of Tropical Medicine,
Pembroke Place, Liverpool L3 5QA, UK
e-mail: nickbeeching@gmail.com
Tel.: ?441517063835

Ebola viruses are single-stranded RNA filoviruses which

are maintained in nature in fruit bats [1]. The genus
includes five strains that are clinically distinguished by
their usual geographic location and severity of disease in
humans. The Reston strain does not appear to cause
human disease, and asymptomatic human infections can
also occur with other strains. The current West African
outbreak is caused by the Zaire strain,which is typically
associated with mortality rates of 5090 % [2, 3]. This
short review summarises knowledge about the pathogenesis of organ dysfunction in Ebola virus disease (EVD).
Clinical disease commences after an incubation period
ranging from 2 to 21 days, and is initially non-specific,
with fever, headache, lethargy and myalgia. This progresses to a gastrointestinal stage characterised by
diarrhoea, vomiting and abdominal pain. Hypovolemia,
systemic hypoperfusion and shock are the most obvious
clinical syndromes in inadequately resuscitated patients.
Haemorrhage and haemorrhagic shock occur in a minority
of patients, most commonly due to profound and frequently pre-terminal gastrointestinal haemorrhage. Many
patients have features of systemic inflammatory response
syndrome [46], such as fever, tachycardia and

hyperventilation with less frequent leukopenia. Organ

dysfunction (severe sepsis) and shock are also common;
however, the capillary leak syndrome and subsequent
secondary lung injury and hypoxia are much less apparent
than with typical bacterial sepsis [2, 7], possibly due to
difficulties in achieving adequate replacement for fluid
loss in endemic treatment settings. Hyperventilation
usually occurs in compensation for metabolic acidosis,
rather than primary lung involvement with pneumonitis or
pneumonia. C-reactive protein levels are often normal,
but ferritin levels are raised, especially in those with
bleeding and/or a fatal outcome [7]. Other non-specific
markers of poor outcome include low serum albumin and
calcium levels. The extent of multi-organ dysfunction
syndrome in EVDmost commonly involving the kidneys, liver and coagulation systemvaries from mild
dysfunction to irreversible organ failure and death, typically by the end of the second week of illness (Fig. 1).
The pathogenesis of EVD in humans remains poorly
understood. The usual study model is infection of nonhuman primates, while other valuable insights gained
from rodent models are constrained by differences in
clinical features [8]. A common pathogenic feature of

Ebola virus

Cytolytic infection
Inhibtion of innate
immune responses

Parenchymal cells
(eg, hepatocytes)

Dendritic cells

MCP-1
IL8

Inhibition of
adaptive responses
Monocytes/macrophages

Endothelial cells
?sGP

Mediators

Activation
Structural re-organisation

TNF
IL10
IL1RA
IL1
IL6
IFNs
Tissue factor

IFN /IL10
Lymphocytes

Loss of adhesion
Intravascular coagulation
Vascular leakage

Coagulopathy

Apoptosis

Fig. 1 A model of the pathogenesis of filoviral haemorrhagic fever,

based on studies of Zaire Ebola virus infection. Infection causes
lysis of monocytes/macrophages, dendritic cells, and hepatocytes
and suppresses innate immune responses in these cells, aiding
further dissemination. Direct injury to infected cells is accompanied
by indirect effects that are mediated by pro-inflammatory and antiinflammatory effector molecules, including interleukin 1 (IL1),
interleukin 6 (IL6), TNF, interleukin 10 (IL10), and type I
interferons (IFN). The severe illness results from the combined
effects of widespread viral cytolysis and massive release of

proinflammatory mediators. Proinflammatory cytokines and chemokines are also produced by activated endothelial cells, resulting
in a feedback loop to the monocytes/macrophages. Lymphocyte
apoptosis is also apparently brought about through effects of
proinflammatory mediators; it may contribute to immunosuppression by weakening adaptive immune responses. The cell-surface
expression of tissue factor by virus-infected monocytes/macrophages induces disseminated intravascular coagulation.
MCP monocyte chemoattractant protein; IL1RA interleukin-1
receptor antagonist. From Ref. [10], with permission

viral haemorrhagic fever viruses is their ability to disable

the host immune response by attacking and manipulating
the cells that initiate the antiviral response [9, 10]. End
organ dysfunction in EVD results from a combination of
direct injury of virus-infected tissues and the indirect
effects of the immune response. Within an outbreak, viral
strain variation is limited and host response is the main
determinant of outcome [1]. Recovery from Ebola infection is associated with early and well-regulated
inflammatory responses, including early antibody

production, reduced T cell apoptosis and more rapid

clearance of viraemia compared to fatal cases [2, 7, 9, 10].
The virus can evade clearance by abrogating the specific
immune response, and may persist in survivors in sanctuary sites such as the testes. Immune complex
phenomena such as uveitis are reported during recovery
[1, 11].
Studies in non-human primates experimentally infected
with Zaire Ebola virus suggest that the virus binds to
lectins and other surface receptors, and that antigen-

presenting cells such as monocytes, macrophages and

dendritic cells are the preferred early sites of replication
[912]. These initially spread through the lymphatic
system including the liver and spleen, following which
the virus is widely distributed, and as a result body fluids
and tissue remain highly infective, even after death.
A tightly regulated balance of pro- and anti-inflammatory cytokine response appears important for
elimination of invading pathogens and restriction of
excessive tissue damage due to inflammation [7, 9].
Sepsis-induced organ injury develops when the initial
host response to infection becomes amplified and subsequently deregulated, leading to an imbalance between
pro-inflammatory and anti-inflammatory responses [46].
In EVD, infection is characterised by up-regulation of
inflammatory mediators such as interferon-gamma (IFNgamma), IFN-alpha, interleukin-2 (IL-2), IL-6, IL-10,
interferon-inducible proteins and tumour necrosis factor
alpha (TNFa) [7, 13, 14]. Infection or activation of
endothelial cells is suggested by raised levels of soluble
intracellular adhesion molecule 1 (ICAM) and thombomodulin, which, together with cytokine effects, leads to
the loss of vascular integrity, although a direct cytopathic
effect on the vascular endothelium is less frequently seen
[2, 7, 10, 13]. Ebola virus infection is also associated with
an early loss of lymphocytes, due to bystander apoptosis
and the dysregulation of coagulopathy that results in
haemorrhage [10, 11, 15].
Haemorrhagic manifestations vary in severity and
include conjunctival injection, melaena, haematemesis
and bleeding from venepuncture and cannula sites, all
poor prognostic signs [3]. Fatal cases are often associated
with pre-terminal large upper and lower gastrointestinal
haemorrhage, but haemorrhage may not be an independent risk factor for death [7]. Thrombocytopenia,
consumption of clotting factors and increased concentrations of fibrin degradation products are features of
coagulopathy that occurs in EVD [2], similar to other
viral haemorrhagic fevers such as Crimean-Congo
haemorrhagic fever [16], in which severe cases are consistent with the clinical syndrome of disseminated
intravascular coagulation (DIC). As seen in non-human
primate models of EVD, D-dimer levels were 4-fold
higher in fatal cases than in patients who survived [17].
Conversely, high levels of soluble CD40 ligand
(sCD40L), produced by activated platelets, are found in
survivors [7]. The mechanisms responsible for producing
these coagulation disorders are not fully understood, but
release of tissue factors from infected macrophages and
monocytes, impaired production of coagulation factors
due to hepatocellular necrosis and a dysregulated fibrinolytic system probably all contribute [2, 7].
Renal dysfunction and acute kidney injury are common
and often reversible with appropriate fluid management.
Levels of urea and creatinine progressively increase in
fatal cases, peaking 68 days after onset. Urea and

creatinine blood levels in non-fatal cases are much lower

than in patients who have died [7, 17]. Acute kidney
injury is combined with inadequate oral intake due to
profound lethargy. Subsequent renal injury may arise due
to viral or secondary bacterial sepsis resulting in established acute tubular necrosis. Microvascular renal
thrombus deposition associated with DIC may also contribute to acute kidney dysfunction. Background levels of
untreated chronic renal failure in older patients and late
presentation may contribute to a poorer outcome in these
groups.
Various degrees of hepatocellular inflammation have
been reported in human cases, and hepatocellular necrosis
is evident at autopsy in non-human primates. Hepatocellular lesions are generally not thought extensive enough to
be the primary cause of death [2], but reduced production
of coagulation factors may contribute to haemorrhagic
manifestations. Jaundice is not frequently reported and
liver function tests including bilirubin and alkaline
phosphatase are generally not as elevated as s transaminase levels. This suggests that fulminant hepatic failure
does not play as prominent a role in disease pathogenesis
as in other haemorrhagic fevers such as yellow fever.
Impaired secretion of hormones by virus-infected
adrenal cortical cells may contribute to hypotension, renal
sodium loss and accompanying hypovolemia. Significant
viral infiltration and necrosis of the adrenal glands has
been demonstrated in animal models and this warrants
further investigation. Pancreatitis can occur in severe
cases and blood amylase levels are significantly increased
in fatal cases, peaking 68 days after clinical illness onset
[17]. There are few data on neurological invasion by
virus, and the confusion and occasional aggression seen in
severely ill patients may reflect metabolic encephalopathy
or direct neurotropism. Hiccups, possibly of central origin, are anecdotally a poor prognostic sign [3].
There appears to be little association between gender
and outcome, except in pregnancy. The mortality in
children resembles that of younger adults but is higher in
very young children and infants. Young children manifest
more respiratory and gastrointestinal features but less
haemorrhage or confusion than adults [18]. Older adults
and those with comorbidities do worse, but limited data
do not suggest a major effect of HIV positivity on prognosis [2, 6, 7].
In summary, the pathogenesis of EVD shows both
similarities with and differences from other causes of viral
haemorrhagic fever or bacterial sepsis. Systematic prospective observational studies are essential to clarify the
pathogenesis and pathophysiology of disease in humans
and to inform the development of evidence-based clinical
scoring systems and management algorithms, as well as
the evaluation of novel therapeutic agents [19]. Improving
access to basic supportive care is essential. The role and
possible benefit of more aggressive critical care interventions continue to be debated [20].

Acknowledgments Drs Fletcher and Fowler both provide assistance to Ebola Treatment Centres in West Africa, supported by the
World Health Organization. Dr Fletcher receives support from the
Wellcome Trust and from the Ministry of Defence. Dr Fowler is a
clinician scientist of the Heart and Stroke Foundation (Ontario,
Canada). Dr Beeching is partially supported by a National Institute
of Health Research grant to the Health Protection Research Unit in
Emerging and Zoonotic Infections, a collaboration between the

University of Liverpool, Liverpool School of Tropical Medicine

and Public Health England. Views expressed are those of the
authors.
Conflicts of interest On behalf of all authors, the corresponding
author states that there is no conflict of interest.

References
1. Leroy EM, Gonzalez J-P, Baize S
(2011) Ebola and Marburg
haemorrhagic fever viruses: major
scientific advances, but a relatively
minor public health threat for Africa.
Clin Microbiol Infect 17:964976. doi:
10.1111/j.1469-0691.2011.03535.x
2. Feldmann H, Geisbert TW (2011) Ebola
haemorrhagic fever. Lancet
377:849862. doi:
10.1016/S0140-6736(10)60667-8
3. WHO Ebola Response Team (2014)
Ebola virus disease in West Africathe
first 9 months of the epidemic and
forward projections. N Engl J Med.
371:14811495. doi:
10.1056/NEJMoa1411100
4. Cohen J (2002) The
immunopathogenesis of sepsis. Nature
420:885891
5. Angus DC, van der Poll T (2013)
Severe sepsis and septic shock. N Engl
J Med 369:840851. doi:
10.1056/NEJMra1208623
6. Dellinger RP, Levy MM, Rhodes A,
Annane D, Gerlach H, Opal SM et al
(2013) Surviving sepsis campaign:
international guidelines for
management of severe sepsis and septic
shock: 2012. Intensive Care Med
39(2):165228. doi:
10.1007/s00134-012-2769-8
7. McElroy AK, Erickson BR, Flietstra
TD, Rollin PE, Nichol ST, Towner JS,
Spiropolou CF (2014) Ebola
hemorrhagic fever: novel biomarker
correlates of clinical outcome. J Infect
Dis 210(4):558566. doi:
10.1093/infdis/jiu088
8. Bente D, Gren J, Strong JE, Feldmann
H (2009) Disease modeling for Ebola
and Marburg viruses. Dis Model Mech
2:1217. doi:10.1242/dmm.000471

9. Geisbert TW, Jahrling PB (2004) Exotic

emerging viral diseases: progress and
challenges. Nature Med 10(Suppl
12):S110121. doi:10.1038/nm1142
10. Mahanty S, Bray M (2004)
Pathogenesis of filoviral haemorrhagic
fevers. Lancet Infect Dis 4(8):487498
11. Mohamadzadeh M, Chen L,
Schmaljohn AL (2007) How Ebola and
Marburg viruses battle the immune
system. Nat Rev Immunol 7:556567.
doi:10.1038/nri2098
12. Geisbert TW, Young HA, Jahrling PB,
Davis KJ, Larsen T, Kagan E, Hensley
LE (2003) Pathogenesis of Ebola
hemorrhagic fever in primate models:
evidence that hemorrhage is not a direct
effect of virus-induced cytolysis of
endothelial cells. Am J Pathol
163:23712382
13. Villinger F, Rollin PE, Brar SS,
Chikkala NF, Winter J, Sundstrom JB,
Zaki SR, Swanepoel R, Ansari AA,
Peters CJ (1999) Markedly elevated
levels of interferon (IFN)-gamma, IFNalpha, interleukin (IL)-2, IL-10, and
tumor necrosis factor-alpha associated
with fatal Ebola virus infection. J Infect
Dis 179(Suppl 1):S188191. doi:
10.1086/514283
14. Hensley LE, Young HA, Jahrling PB,
Geisbert TW (2002) Proinflammatory
response during Ebola virus infection of
primate models: possible involvement
of the tumor necrosis factor receptor
superfamily. Immunol Lett 80:169179.
doi:10.1016/s0165-2478(01)00327-3
15. Reed DS, Hensley LE, Geisbert JB,
Jahrling PB, Geisbert TW (2004)
Depletion of peripheral blood T
lymphocytes and NK cells during the
course of ebolahemorrhagic fever in
cynomolgus macaques. Viral Immunol
17:390400. doi:
10.1089/vim.2004.17.390

16. Leblebicioglu H, Bodur H, Dokuzoguz

B, Elaldi N, Guner R, Koksal I, Kurt H,
Senturk GC (2012) Case management
and supportive treatment for patients
with Crimean-Congo hemorrhagic
fever. Vector Borne Zoonotic Dis
12:805811. doi:
10.1089/vbz.2011.0896
17. Rollin PE, Bausch DG, Sanchez A
(2007) Blood chemistry measurements
and D-dimer levels associated with fatal
and nonfatal outcomes in humans
infected with Sudan Ebola Virus.
J Infect Dis 196(Suppl 2):S364371
18. Mupere E, Kaducu OF, Yoti Z (2001)
Ebola haemorrhagic fever among
hospitalised children and adolescents in
nothern Uganda : epidemiologic and
clinical observations. Afr Hlth Sci 1(2):
6065.
http://www.ncbi.nlm.nih.gov/pmc/
articles/PMC2141551/
19. Goodman JL (2014) Studying Secret
Serumstoward safe, effective Ebola
treatments. N Engl J Med
371:1081089. doi:
10.1056/NEJMp1409817
20. Fowler RA, Fletcher T, Fischer WA,
Lamontagne F, Jacob S, Brett-Major D
et al (2014) Caring for critically ill
patients with Ebola virus disease.
Perspectives from West Africa. Am J
Respir Crit Care Med 190(7):733737